Anastasi S, Baietti M F, Frosi Y, Alemà S, Segatto O
Department of Experimental Oncology, Laboratory of Immunology, Regina Elena Cancer Institute, Rome, Italy.
Oncogene. 2007 Dec 13;26(57):7833-46. doi: 10.1038/sj.onc.1210590. Epub 2007 Jun 18.
Physiological signalling by the epidermal growth factor receptor (EGFR) controls developmental processes and tissue homeostasis, whereas aberrant EGFR activity drives oncogenic cell transformation. Under normal conditions, the EGFR must therefore generate outputs of defined strength and duration. To this aim, cells balance EGFR activity via different modalities of negative signalling. Increasing attention is being drawn on transcriptionally controlled feedback inhibitors of EGFR, namely RALT/MIG6, LRIG1, SOCS4 and SOCS5. Genetic studies in mice have revealed the essential role of Ralt/Mig6 in regulating Egfr-driven skin morphogenesis and tumour formation, yet the mechanisms through which RALT abrogates EGFR activity are still undefined. We report that RALT suppresses EGFR function by inhibiting its catalytic activity. The evolutionarily conserved ErbB-binding region (EBR) is necessary and sufficient to carry out RALT-dependent suppression of EGFR kinase activity in vitro and in intact cells. The mechanism involves binding of the EBR to the 953RYLVIQ958 sequence, which is located in the alphaI helix of the EGFR kinase and has been shown to participate in allosteric control of EGFR catalytic activity. Our results uncover a novel mechanism of temporal regulation of EGFR activity in vertebrate organisms.
表皮生长因子受体（EGFR）的生理信号传导控制着发育过程和组织稳态，而异常的EGFR活性则驱动致癌性细胞转化。因此，在正常情况下，EGFR必须产生具有特定强度和持续时间的输出信号。为了实现这一目标，细胞通过不同形式的负向信号传导来平衡EGFR的活性。人们越来越关注EGFR的转录调控反馈抑制剂，即RALT/MIG6、LRIG1、SOCS4和SOCS5。小鼠的遗传学研究揭示了Ralt/Mig6在调节Egfr驱动的皮肤形态发生和肿瘤形成中的重要作用，然而RALT消除EGFR活性的机制仍不明确。我们报告称，RALT通过抑制EGFR的催化活性来抑制其功能。进化上保守的ErbB结合区域（EBR）在体外和完整细胞中对于进行RALT依赖的EGFR激酶活性抑制是必要且充分的。该机制涉及EBR与953RYLVIQ958序列的结合，该序列位于EGFR激酶的αI螺旋中，并且已被证明参与EGFR催化活性的变构调节。我们的结果揭示了脊椎动物中EGFR活性的一种新的时间调控机制。
